Submissions for variant NM_000179.3(MSH6):c.2876G>A (p.Arg959His)

gnomAD frequency: 0.00001  dbSNP: rs757653982

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165726	SCV000216467	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	The p.R959H variant (also known as c.2876G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2876. The arginine at codon 959 is replaced by histidine, an amino acid with highly similar properties. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as uncertain significance (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204562	SCV000261435	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 959 of the MSH6 protein (p.Arg959His). This variant is present in population databases (rs757653982, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 186181). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506421	SCV000601544	uncertain significance	not specified	2016-10-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000662759	SCV000785553	uncertain significance	Lynch syndrome 5	2017-11-14	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758673	SCV000887444	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.2876G>A has a 92.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Color Diagnostics, LLC DBA Color Health	RCV000165726	SCV001348347	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 959 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with colorectal cancer that displayed high microsatellite instability with intact MSH6 protein but loss of of MLH1 and PMS2 proteins via immunohistochemistry analysis (PMID: 29596542). This variant has been identified in 5/281452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001840209	SCV002099620	uncertain significance	not provided	2024-03-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27300758, 25164765, 26110843, 26648449, 17531815, 21120944, 29596542)
Myriad Genetics, Inc.	RCV000662759	SCV004018918	uncertain significance	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003462188	SCV004195688	uncertain significance	Endometrial carcinoma	2023-07-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000758673	SCV004838912	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 959 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individual suspected of having Lynch syndrome (PMID: 26648449, 29596542). This variant has been identified in 5/281452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506421	SCV005205042	uncertain significance	not specified	2024-06-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2876G>A (p.Arg959His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250052 control chromosomes, predominantly at a frequency of 3.5e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2876G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 186181). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001840209	SCV005411717	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	PP3, PM2_moderate